tbuckley/cabot-search huggingface dataset:
Abstract 5081: Proteomic analysis of ascites- and cancer cell-derived EVs for identifying ovarian cancer diagnostic biomarkers
Authors: Wenyu Wang, Dohyun Han, Yong Sang Song
Journal: Cancer Research (2022)

Abstract Ovarian cancer is the most lethal gynecologic cancer in the world. Most patients are diagnosed at advanced stages with the formation of ascites. Extracellular vesicles (EVs) have been elucidated to play a pivotal role in cancer development and progression, also emerging as promising resources for clinical biomarkers in liquid biopsy. In this study, we aim to identify cancer-specific protein biomarkers in ascites-derived EVs for ovarian cancer diagnosis. Malignant ascites from high grade ovarian cancer patients (HGSOC) and benign peritoneal fluids from female patients with benign gynecologic diseases were collected with informed consent. EVs were isolated from these biofluids using the Exoquick kit. Meanwhile, HGSOC cell lines and normal cell lines were cultured in conditioned media supplemented with EVs-depleted FBS. EVs were isolated from the culture media. Proteins were extracted from EVs and fragmented into peptides. Tandem mass tag (TMT) hyper multiplex quantitation assay was carried out to detect the EV proteomic profiling. EVs isolated from biofluids and cell culture media were identified as double-membrane nanoparticles sizing ranging from 30nm to 200nm. Proteomic analysis of biofluids-derived EVs showed that malignant ascites-derived EVs displayed different proteomic profiling compared to benign peritoneal fluids-derived EVs. The differently expressed proteins between malignant ascites-derived EVs and benign peritoneal fluids-derived EVs were defined as candidate EV protein biomarkers. In addition, proteins that were expressed in at least one cancer cell line-derived EVs but not expressed in normal cell line-derived EVs were also identified as ovarian cancer-specific proteins. A diagnostic model constructed based on the integrative analysis of candidate EV protein biomarkers and ovarian cancer-specific proteins yielded a good discrimination ability between benign and cancer patients.In conclusion, this study demonstrates the distinct proteomic profiling in ascites- and cancer cell-derived EVs in ovarian cancer, which sheds new light on implementing EV proteins as a potential diagnostic strategy in clinical settings. Citation Format: Wenyu Wang, Dohyun Han, Yong Sang Song. Proteomic analysis of ascites- and cancer cell-derived EVs for identifying ovarian cancer diagnostic biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5081.
Abstract 768: Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes
Authors: Ju-Seog Lee, Sun Young Yim, Sung Hwan Lee, Yun Seong Jeong
Journal: Cancer Research (2022)

Abstract Background &amp; Aims: While many studies revealed transcriptomic subtypes of hepatocellular carcinoma (HCC), they are not translated to the clinic yet due to lack of consensus. We aim to examine consensus of transcriptomic subtypes and uncover their clinical significance. Methods: We integrated 15 previously established transcriptomic signatures for HCC to uncover consensus subtypes. We also developed and validated a robust predictor of consensus subtype with 100 genes (PICS100). Informatics and statistics approaches were applied to find clinical relevant association of genomic features. Patient derived xenograft (PDX) models were used for testing hypothesis from analysis of transcriptomic data. Results: We identified 5 clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high HNF4A activity. We also identified potential serum biomarkers that can stratify patients into 5 subtypes. Conclusions: Five HCC subtypes are associated with potential response to treatments and highly conserved in pre-clinical models, providing a framework for selecting the most appropriate models for preclinical studies of new drugs and potentially for future clinical trials. Citation Format: Ju-Seog Lee, Sun Young Yim, Sung Hwan Lee, Yun Seong Jeong. Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 768.
Abstract 3891: Efficacy of dinaciclib in hepatoblastoma through inhibition of cyclin dependent kinases
Authors: Rohit K. Srivastava, Roma Patel, Andres F. Espinoza, Yang Yu, Richard S. Whitlock, Samuel Larson, Andrew Badachhape, Jianhua Yang, Sarah E. Woodfield, Sanjeev A. Vasudevan
Journal: Cancer Research (2022)

Abstract Introduction: Hepatoblastoma (HB) is the most frequent liver malignancy of childhood with an annual incidence of 1.5 per million and a survival rate less than 50%. Due to significant side effects and ineffectiveness of standard chemotherapy for relapse refractory disease, the treatment options are now shifting towards targeted therapies. Cyclin-dependent kinases (CDKs) are potential cancer therapeutic targets because of their critical role in promoting cell growth and regulating transcriptional processes. This study aims to assess the therapeutic efficacy of dinaciclib, cyclin-dependent kinase inhibitor, with HB in preclinical in vitroand in vivo models. Method: Dinaciclib was tested in patient derived cell lines (PDCL) from different patient derived xenograft (PDX) models using CellTiter-Glo Luminescent Viability assays. Dinaciclib was also assayed in vitro for cytotoxicity (MTT assay) and proliferation (CCK-8 assay). Differential expression of CDKs was checked by microarray analysis between normal liver and HB patients. Results were confirmed by immunoblotting assays. Immunoblotting assays were also used to see the effect of dinaciclib on CDK 1/2/5/9 and to assess the induction of apoptosis (PARP cleavage) in vitro. Dinaciclib was also tested in our orthotopic PDX models of high-risk HB. MRI and alpha-fetoprotein (AFP) ELISA were done to evaluate tumor growth. Tumor weights and volumes, as well as, immunohistochemistry were also used to assess effects of dinaciclib in vivo. Result: Dinaciclib suppressed cell proliferation and viability in a dose-dependent manner in all HB cell lines tested with IC50 in the low micromolar range (HepG2- 3.75; HepT1- 0.007; Huh6- 1.42; HB17- 0.72). Microarray analysis showed significant upregulation of CDK1 (p=0.0003), CDK2 (p=0.00023) and CDK9 (p=0.015) in HB patient samples, however, immunoblotting with dinaciclib-treated cells showed decreased expression of CDKs 1/2/5/9 as well as induction of apoptosis. Dinaciclib also showed in vivo inhibition of tumor growth compared to placebo in both PDX models (HB47: relative tumor volume p = 0.03, T/C ratio= 0.36, tumor weight p = 0.02; HB52: relative tumor volume p = 0.06, T/C ratio= 0.16, tumor weight p = 0.07). Conclusion: Dinaciclib treatment showed promising effects with preclinical HB cell lines and PDX models. Citation Format: Rohit K. Srivastava, Roma Patel, Andres F. Espinoza, Yang Yu, Richard S. Whitlock, Samuel Larson, Andrew Badachhape, Jianhua Yang, Sarah E. Woodfield, Sanjeev A. Vasudevan. Efficacy of dinaciclib in hepatoblastoma through inhibition of cyclin dependent kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3891.
Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa
Authors: Da Meng, Sara D. Ragi, Stephen H. Tsang
Journal: Molecular Therapy (2022)

(Molecular Therapy 28, 2139–2149; October 2020) In the originally published version of this article, it was stated that “The National Institute of Standards and Technology has set the limit for an acceptable CRISPR off-targeting rate in patients at 25%. [56–59]” This percentage is incorrect, so we have elected to redact it entirely from the review. The authors regret this error. Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis PigmentosaMeng et al.Molecular TherapyAugust 26, 2020In BriefThere have been recent advances in gene replacement therapies for autosomal recessive and X-linked inherited retinal disorders, but treating autosomal dominant diseases remains challenging. Tsang and colleagues highlight recent developments in gene therapy for rhodopsin-mediated autosomal dominant retinitis pigmentosa. The therapeutic strategies discussed are applicable to all autosomal dominant disorders. Full-Text PDF Open Archive
Abstract LB505: Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor
Authors: John M. Ketcham, David M. Briere, Aaron C. Burns, James G. Christensen, Robin J. Gunn, Jacob Haling, Anthony Ivetac, Shilpi Khare, Jon Kuehler, Svitlana Kulyk, Jade Laguer, John D. Lawson, Krystal Moya, Natalie Nguyen, Peter Olson, Lisa Rahbaek, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Darin Vanderpool, Xiaolun Wang, Matthew A. Marx
Journal: Cancer Research (2022)

Abstract KRAS mutations are the most common activating mutations in human cancer that ultimately lead to hyperactivation of the MAPK pathway and uncontrolled growth. KRAS functions as a small GTPase that cycles through its GTP-loaded “on” state and its GDP-loaded “off” state, a highly regulated process that is crucial for normal cell proliferation and survival. The guanine nucleotide exchange factor (GEF) SOS1 plays a critical role in this process by regulating the “on/off” state of KRAS. The protein-protein interaction between SOS1 and KRAS facilitates turnover of KRAS from the GDP-loaded inactive state to its activated and GTP-loaded state, a critical step to enable productive KRAS effector binding and activation of downstream signaling. The KRASG12C inhibitor, adagrasib (MRTX849), irreversibly binds to the GDP-loaded inactive conformation of KRASG12C and has recently shown encouraging clinical activity across several cancer types. As adagrasib binds preferentially to the inactive state of KRAS, blockade of SOS1 is anticipated to shift KRASG12C into the adagrasib-susceptible GDP-loaded state. Furthermore, this combination strategy could be used to target other mutant-driven cancers within the MAPK pathway using the appropriate KRASmut inhibitors and/or inhibitors of other targets within the MAPK pathway including MEK or EGFR. MRTX0902 was identified using iterative structure-based design as a selective inhibitor of SOS1 that demonstrates an IC50 value of 2 nM in a SOS1 HTRF binding assay and 30 nM in an MKN1 cellular assay. In pharmacokinetic evaluation across species, MRTX0902 demonstrated low extraction ratios and moderate to high bioavailability in mice, rats, and dogs. In preclinical models, MRTX0902 augmented the antitumor activity of adagrasib and other selected therapies. The design, discovery, and preclinical characterization of the potential best-in-class candidate MRTX0902 will be described. Citation Format: John M. Ketcham, David M. Briere, Aaron C. Burns, James G. Christensen, Robin J. Gunn, Jacob Haling, Anthony Ivetac, Shilpi Khare, Jon Kuehler, Svitlana Kulyk, Jade Laguer, John D. Lawson, Krystal Moya, Natalie Nguyen, Peter Olson, Lisa Rahbaek, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Darin Vanderpool, Xiaolun Wang, Matthew A. Marx. Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB505.
Abstract 4018: Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study
Authors: Isabel Porth, Philip Weidner, Sylvie Lorenzen, Wilko Weichert, Thorsten Oliver Götze, Sven Perner, Kim Luley, Daniela Hirsch, Ralf-Dieter Hofheinz, Diana B. Peckys, Zahra Mostajeran, Niels de Jonge, Timo Gaiser
Journal: Cancer Research (2022)

Abstract Since 2010, Trastuzumab combined with chemotherapy is the standard treatment for patients with HER2 (ERBB2) positive advanced or metastatic gastric and gastroesophageal junction cancer (GGEJ). While few patients show long-term response to the treatment, most suffer from rapid disease progression. Several studies revealed that genomic alterations, gene expression changes and altered HER2 signaling activity contribute to impaired therapy response. However, the underlying mechanism remains unclear. The aim of this research project is to analyze differences between patients with long and short progression-free survival by utilizing combined genetic, histologic, clinical and gene expression data. We collected a retrospective German patient cohort (n=20) including patients with HER2 positive advanced GGEJ who received Trastuzumab combined with chemotherapy. Using archival samples that were obtained prior to Trastuzumab treatment, we created a dataset including clinical information, histologic assessment, immunostaining, target amplicon sequencing (TAS; 409 gene panel) and human transcriptome data using the Affymetrix platform. To analyze the TAS sequencing data, we generated an automated analysis pipeline, which detects single nucleotide variants (SNV) and copy number alterations (CNA). Information about genomic alteration will be correlated with pathway and gene set enrichment analysis (GSEA) from the Affymetrix data. Furthermore, the data will be supported by investigating the functional status of HER2 in patient samples via electron microscopy. The results of this study could give insights on how genetic and transcriptomic alterations are connected to long-term Trastuzumab therapy response in HER2 positive GGEJ patients. This could potentially support therapy decision in personalized medicine. Citation Format: Isabel Porth, Philip Weidner, Sylvie Lorenzen, Wilko Weichert, Thorsten Oliver Götze, Sven Perner, Kim Luley, Daniela Hirsch, Ralf-Dieter Hofheinz, Diana B. Peckys, Zahra Mostajeran, Niels de Jonge, Timo Gaiser. Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4018.
Abstract 2166: Ibuprofen induces ferroptosis to potentiate antitumor immunity
Authors: Ronan Talty, Michelle Ferreira, Irina Krykbaeva, Marcus Bosenberg
Journal: Cancer Research (2022)

Abstract Ferroptosis is an iron-dependent regulated cell death pathway that has recently emerged as a promising target for cancer therapy. PTGS2 has been identified as a marker of ferroptosis due to its upregulation in cells after treatment with ferroptosis inducers. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the protein product of PTGS2 and have been shown to enhance antitumor immunity. We hypothesized that NSAIDs induce ferroptosis and that this mechanism is essential for their effect on antitumor immunity. To test this, we first determined that ibuprofen and other NSAIDs induce cell death in YUMMER-1.7 melanoma and MC38 colorectal cancer cells in vitro. Cell death occurred progressively over 24 hours and could be blocked by multiple ferroptosis inhibitors. Treatment with NSAIDs also increased intracellular lipid peroxides and decreased levels of reduced glutathione and ferrous iron. This indicated that ibuprofen and other NSAIDs induce ferroptosis in vitro, so we next evaluated whether ibuprofen also induces ferroptosis in vivo. Analysis of ibuprofen-treated YUMMER-1.7 or MC38 tumors showed increased levels of lipid peroxides and lipid peroxide intermediates, 4-hydroxynonenal and malondialdehyde, compared to untreated tumors. Treatment of tumor-bearing mice with ibuprofen alone resulted in approximately 60% tumor clearance and survival, whereas a combination of multiple ferroptosis inhibitors with ibuprofen completely abrogated this effect. Since it has been demonstrated by that CD8+ T cells can release IFN-γ to induce ferroptosis in tumor cells, we next tested the dependence of the antitumor effect of ibuprofen on CD4+ T cells, CD8+ T cells, and IFN-γ using depleting antibodies. Depletion of any of these was sufficient to prevent the antitumor effect of ibuprofen. Given the need to identify pathways that enhance responses to existing immunotherapies, we determined whether treatment with ibuprofen synergizes with PD-1 checkpoint blockade. The combination of α-PD-1 with ibuprofen resulted in a 100% tumor clearance and survival rate, whereas α-PD-1 or ibuprofen alone resulted in 40% and 60% tumor clearance and survival rates, respectively. Furthermore, treatment with ibuprofen also sensitized α-PD-1-resistant tumors to PD-1 in two distinct models of α-PD-1 resistance. Overall, these findings establish ibuprofen and other NSAIDs as inducers of ferroptosis and underscore the potential for ferroptosis inducers to be used in combination with existing immunotherapy regimens. Citation Format: Ronan Talty, Michelle Ferreira, Irina Krykbaeva, Marcus Bosenberg. Ibuprofen induces ferroptosis to potentiate antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2166.
Abstract 4122: Occurrence of BRAF class II and III alterations is common across solid tumors and is associated with inferior clinical outcomes in NSCLC and melanoma
Authors: Paul L. Severson, Elifnur Yay Donderici, Nicole Zhang, Aleksandra Franovic, Nichol Miller, Eric Martin, Eric Murphy, Richard Williams
Journal: Cancer Research (2022)

Abstract Background: Oncogenic BRAF alterations can be categorized by their distinct structural and signaling properties which lead to activation of the MAPK pathway: class I - kinase active signaling of BRAF mutant monomers; class II - kinase active signaling of BRAF mutant dimers; and class III - kinase impaired BRAF that signals via RAS-dependent, heterodimers containing wild-type RAF. There are currently no approved BRAF targeted therapies for patients whose tumors bear BRAF class II or III alterations. This research utilizes the GuardantINFORM࣪ clinical-genomic database to assess the real-world occurrence and outcomes of patients with oncogenic BRAF alterations by distinct classes across solid tumors.​ Methods: This observational study utilized a database containing clinical and genomic data from ~160,000 cancer patients with ctDNA profiling by the Guardant360 assay. Patients were categorized using a broad list of known and putative class I, II or III BRAF alterations compiled from published sources. Patients were stratified by BRAF mutant class for real-world overall survival analyses. Results: The analysis identified a cohort of over 5,890 patients with oncogenic BRAF alterations. Class II and III alterations were present in more than 2% of all ctDNA positive patients and made up approximately 55% of all the oncogenic BRAF alterations. Class II and III accounted for 65%, 30% and 20% of oncogenic BRAF alterations in NSCLC, CRC and melanoma respectively. NSCLC and melanoma patients with class II or III BRAF alterations experienced shorter overall survival relative to patients with class I alterations. Conclusions: The analysis of this large real-world dataset identified a substantial number of cancer patients with BRAF class II and III alterations. NSCLC and melanoma patients with BRAF class II and III alterations experienced inferior clinical outcomes and represent a population that could benefit from novel targeted therapies. Overall survival in NSCLC and melanoma patients with BRAF class I, II or III alterations Cohort Median OS Months (%95 CI) Unadjusted P-value Class I Class II Class III I vs II I vs III II vs III NSCLC (n=938) 44.8 (37.5,52.8) 34.4 (27.5,41.5) 32.3 (28.4,40.9) 0.006 0.0126 0.6611 Melanoma (n=333) 46.5 (42.3,65.5) 28.5 (8.6,30.3) 30.5 (12.5,73.8) 0.0008 0.0165 0.6529 Citation Format: Paul L. Severson, Elifnur Yay Donderici, Nicole Zhang, Aleksandra Franovic, Nichol Miller, Eric Martin, Eric Murphy, Richard Williams. Occurrence of BRAF class II and III alterations is common across solid tumors and is associated with inferior clinical outcomes in NSCLC and melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4122.
Abstract LB103: Novel DNA-based-T-cell-activation for the generation of chimeric antigen receptor T cells with enhanced anti-leukemia cytotoxicity
Authors: Mehdi Benzaoui, Sooraj R. Achar, Vandana Keskar, Anup Sood, Brian M. Davis, Steven L. Highfill, Grégoire Altan-Bonnet, Christopher D. Chien, Naomi Taylor
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable results in the treatment of hematological malignancies. However, several challenges remain, including achieving predictable efficacy and safety profiles and extending this approach to solid tumors. As such, the development of approaches that generate engineered T cells with superior persistence and efficacy are needed. Currently, the generation of CAR-T requires that they be activated and expanded ex vivo, generally via beads coated with anti-CD3/anti-CD28 mAbs. T cell activation provides three fundamental signals; (i) primary triggering of TCR signals; (ii) secondary co-stimulatory signals and, (iii) synthesis of cytokines to direct T cell expansion and differentiation. We hypothesize that a CAR-T response can be modulated by tuning the: (i) pattern, (ii) magnitude and, (iii) duration of the input T cell activation signals. To this end, we used a novel, soluble, tunable activation platform based on DNA hybridization - utilizing concatenated single stranded DNA (ssDNA) polymers to cluster complementary oligonucleotide-modified antibodies targeted at T-cell surface receptors. This DNA-Based-T-cell-Activation (DBTA) platform was compared with conventional bead-bound CD3/CD28 antibodies (Dynabead) in the generation and function of T cells engineered to express a CD19-targeted CAR harboring a 4-1BB co-stimulatory domain. The two methods did not result in any significant differences in CAR-T expansion nor in memory/activation phenotypes. Notably, though, these cells exhibited higher cytokine secretion in response to CAR stimulation, and in vitro killing of DBTA-generated CART was significantly higher than that of bead-activated CART. Indeed, only the former showed cytotoxicity against Nalm6 leukemic cells expressing low levels of the CD19 target antigen CART. Furthermore, in an in vivo NSG model with Nalm6 leukemia, the adoptive transfer of low numbers of DBTA-generated CART (2e6) resulted in leukemia eradication and delayed leukemia relapse. Mechanistically, the enhanced function of DBTA-generated CAR was associated with increased metabolic activity in the pre-infusion product. These results suggest that calibrating the activation potential of CAR-T cells can result in the generation of a product with enhanced therapeutic potential. Citation Format: Mehdi Benzaoui, Sooraj R. Achar, Vandana Keskar, Anup Sood, Brian M. Davis, Steven L. Highfill, Grégoire Altan-Bonnet, Christopher D. Chien, Naomi Taylor. Novel DNA-based-T-cell-activation for the generation of chimeric antigen receptor T cells with enhanced anti-leukemia cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB103.